In spite of the abundance and availability of numerous oral psychiatric pharmaceuticals, there is an unmet need in the pharmaceutical marketplace for fast-acting therapies for the pro re nata (p.r.n.; “as needed”) treatment of symptoms of acute anxiety and panic. The present invention addresses multiple aspects of this unmet medical need via the following beneficial features, among others.
The present invention is focused primarily toward p.r.n. treatments for the symptoms of acute anxiety and panic. The same or similar treatments may also provide benefit with regard to an even broader group of psychiatric conditions or disorders, such as alcohol addiction and/or withdrawal, drug addiction and/or withdrawal, migraine, headache, and aggression. Effective treatments for the symptoms of acute anxiety and panic per se should coincidentally reduce or remove some of the same somatic and/or psychic symptoms associated with this broader group of psychiatric conditions.
The active pharmaceutical ingredient (API) combinations of the present invention provide complementary pharmacologic benefits by interaction of two types of APIs having two (or more) dissimilar pharmacologic molecular targets. The biochemical pathways of the beta adrenergic receptor and muscarinic receptor gene families are appropriate anxiolytic targets for the symptoms of panic attack (PA), panic disorder (PD), agoraphobia, generalized anxiety disorder, social anxiety disorder (social phobia), performance anxiety (e.g., stage fright), post-traumatic stress, post-traumatic stress disorder (PTSD), post-traumatic anxiety, and shell shock. These anxiety disorders are further delineated within the Diagnostic and Statistical Manual of Mental Disorders (e.g., DSM-5). Furthermore, these distinct biochemical pathways may be appropriate for therapeutic intervention for drug addiction and/or withdrawal, alcohol addiction and/or withdrawal, migraine, headache, and aggression. Those molecular targets can be components of the central nervous system (CNS), the peripheral nervous system, and/or of target somatic tissues (e.g., cardiovascular and gastrointestinal tissues). The appropriate combination of APIs is expected to affect more molecular targets than could be achieved by using a single API alone. Given that the multiplicity of symptoms of PA, PD, anxiety, and anxiety-related disorders are under the regulation of different neurologic, neuroendocrine, and endocrine pathways, it follows that pharmacologic antagonists affecting both the beta adrenergic receptors and muscarinic receptors could suppress more symptoms than could be achieved by a single API alone.
An acute anxiety or panic attack “trigger” circumstance results in the autonomic release of epinephrine (adrenaline), as well as cortisol and norepinephrine. This in turn causes multiple effects consistent with a “fight-or-flight response”. Symptoms include tachycardia (increased heart rate), palpitations (perception of an elevated heart rate and/or of a strong heart beat), hypertension (increased blood pressure), hyperventilation (with reduced blood CO2 and altered pH), dyspnea, mental anxiety, nausea, vomiting, fear, avoidance, trembling (tremors), sweating, headache, among others. Many of the somatic and/or psychic (CNS) symptoms of panic attack are shared in common with social anxiety disorder (social phobia), generalized anxiety disorder, agoraphobia, and PTSD. Therefore, it follows that an effective treatment for the symptoms of panic per se can also be effective against anxiety and anxiety-related disorders.
Some patients anticipate future episodes of panic or acute anxiety based upon his/her history of encounters with a known “trigger” circumstance. A trigger circumstance might be public speaking, a public music performance, flying, driving, a noise, a crowd of people (e.g., agoraphobia), decision-making, an unfamiliar setting, among others. Given the patients' anticipation of a trigger leading toward likely future symptoms, p.r.n. drug treatments of the present invention can be designed for rapid effect, and with the pharmacologic benefits beginning either during or immediately prior to the time when symptoms would be expected to commence.
The lifetime prevalence of PA is 28.3% of the adult US population [1]. The 12-month prevalence of panic disorder (PD) is estimated to be 2.7% of the adult US population [2], with 1.2% considered as “severe” [3]. More than half of affected adults (59.1% or ˜3.8 million) are receiving treatment(s) [4]. Patients affected by PAs are often also affected by the co-morbid conditions of depression [5] and migraines (and other forms of headaches) [6, 7]. In aggregate panic and anxiety are extremely common, affecting nearly 40 million in the US.
The current standards-of-care for PD are oral psychiatric prophylactic pharmaceuticals, including: (1) Selective serotonin reuptake inhibitors (SSRIs), which are considered as the first choice medicines for PD. Examples include Paroxetine (PAXIL®), Sertraline (ZOLOFT®), and Fluoxetine (PROZAC®); (2) Benzodiazepines, such as Clonazepam (KLONOPIN®), Alprazolam (XANAX®), Lorazepam (ATIVAN®)), and Diazepam (VALIUM®); (3) Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as Duloxetine (CYMBALTA®) and Venlafaxine (EFFEXOR®); and (4) other medications, such as Quetiapine (SEROQUEL®), an antipsychotic prescribed for generalized anxiety disorder. These oral therapies are taken daily for the prevention of panic attacks. Some of these drugs are FDA approved for the prophylaxis of PD, such as Paroxetine, Sertraline, Alprazolam, and Clonazepam.
Other anxiety-related disorders are also treated in the same or a similar manner. For instance, social anxiety disorder (social phobia), generalized anxiety disorder, agoraphobia, and post-traumatic stress disorder (PTSD) are also treated using the same or similar oral daily pharmaceutical regimens [8].
The pharmaceutical standards-of-care in routine psychiatric care of PA, PD, anxiety, and anxiety-related disorders involve two key aspects: (1) prophylaxis, rather than treatment of the symptoms per se; and (2) the medications are routinely given as daily oral “maintenance” medications for persistent use (i.e., chronic prophylaxis), rather than as occasional administration “as needed” (p.r.n.) at the time of episodes of symptoms (i.e., acute therapy). The present invention provides an alternative paradigm that goes beyond the current standards-of-care in psychiatric medicine for PA, PD, anxiety, and anxiety-related disorders.
Although oral benzodiazepines have been used as persistent daily medications for the prophylaxis of panic and acute anxiety, they are not reasonable candidates for this alternative “fast-acting” p.r.n. approach of the present invention. Although benzodiazepines are often mistakenly considered to be “fast-acting”, multiple clinical reports indicate otherwise. Zamorski and Albucher stated, “Benzodiazepines should not be used on an as-needed basis for panic disorder. None of the oral benzodiazepines works quickly enough to affect any but the most prolonged panic attacks.”[9] Altamura and coworkers stated recently, “ . . . it would be desirable for the development of new anxiolytic drug(s) that are more selective, fast acting and free from the unwanted effects associated with the traditional benzodiazepines as tolerance or dependence.”[10] Altamura and coworkers also stated regarding benzodiazepines as a class of anxiolytic drugs, “Only lorazepam is currently available in a form suitable for sublingual administration, which was developed in the hope that, by bypassing the gut, a more rapid onset could be achieved similar to that with intramuscular administration. However, Greenblatt et al. [11] found that the sublingual formulation was absorbed at a rate that did not differ significantly from that of regular oral administration of the standard tablets or even from that of sublingual administration of the standard oral tablets.” [10] Thus, benzodiazepines are not suitable for rapid treatment of symptoms of panic attacks or acute anxiety episodes, even when delivered sublingually (mucosally). In conclusion, when “time is of the essence” for therapy, benzodiazepines are inadequate, regardless of the oral or sublingual routes of administration.
Furthermore, SSRIs are considered as the first choice medications for PD prophylaxis, but they require a very slow dose-escalation approach over weeks of time to produce a beneficial effect. Thus, the most common drugs for the indications that are the focus of this invention—benzodiazepines and SSRIs—are not feasible for p.r.n. therapy for rapid symptomatic relief.
Benzodiazepine and SSRI drugs can produce disabling psychic and somatic side effects, such as sedation, lethargy, chemical dependence, tolerance, and sexual dysfunction[9]. As a result of these negative side effects and potential for abuse, benzodiazepines are classified by the U.S. Food and Drug Administration (FDA) as Schedule 4 (IV) “Controlled Substances”. Many physicians and other prescribers (e.g., dentists) are reluctant or prohibited from prescribing benzodiazepines. The present invention does not include either benzodiazepines or SSRIs as APIs. None of the APIs of the present invention are “Controlled Substances” as classified by the U.S. FDA Schedules 1-4.
The present invention encompasses pharmaceutical compositions as combination therapies containing at least one beta adrenergic receptor antagonist (e.g., propranolol, atenolol, or nadolol) and at least one muscarinic receptor antagonist (e.g., scopolamine, diphenhydramine, or meclizine). In an embodiment, a representative combination therapy of interest includes two well-known APIs, scopolamine and a beta blocker, such as propranolol.
Coma et al. (US Application Publication No. 2013/0116215) describe combinations of compounds which are therapeutically effective for treating neurodegenerative disorders. The application refers in general to methods of a “Therapeutic Performance Mapping System” technology. The application does not specifically disclose a combination of propranolol and scopolamine for the treatment of neurodegenerative diseases. Moreover, the application does not relate to the treatment of PA and PD.
Dargelas et al. (US Application Publication No. 2009/0220611) disclose microparticulate systems with modified release of oral active principle(s). The application explains that “coated ‘reservoir’ microparticles” may be used in the treatment of a lengthy list of medical indications, including cardiovascular and nervous system conditions among others, and discloses a lengthy list of APIs, for example, scopolamine or propranolol, which may be coated and formulated as microparticles.
Arora et al. (US Application Publication No. 2011/0281853) and Zembower & Arora (PCT International Publication No. WO 2011/143457) disclose compositions and methods for treating or preventing atrial fibrillation (AF). In particular, the application discloses administration of muscarinic receptor antagonists (e.g., M2-selective muscarinic receptor blockers), alone or in combination with other therapeutic agents (e.g., beta adrenergic receptor blockers), to treat and/or prevent atrial fibrillation. Arora et al. are silent with respect to compositions and methods for treating symptoms associated with PA, PD, anxiety, anxiety-related disorders, or psychiatry in general.
Kukkonen-Harjula and coworkers [12] discloses the cardiovascular effects of oral atenolol, oral scopolamine, or a coincident administration of both drugs in healthy volunteers prior to and during exposure to heat within a sauna. However, this article does not address pharmaceutical compositions and methods for treating PA, PD, anxiety, anxiety-related disorders, or psychiatry in general.
Frenette et al. (PCT International Publication No. WO2012/071573) disclose the use of beta adrenergic receptor antagonists (e.g., propranolol) and muscarinic receptor antagonists (e.g., scopolamine) among a lengthy list of APIs for use as cancer chemotherapies, specifically to inhibit tumor initiation and tumor metastasis.
Holly (US Application Publication No. 2011/0218215) discloses compositions and methods for treating social anxiety including a beta adrenergic receptor antagonist (specifically propranolol) coupled with an antidiarrheal agent (specifically the opioid diphenoxylate). The compositions may optionally include an anticholinergic agent (specifically atropine sulfate), but this is not required. And, the anticholinergic, atropine, is intended to deter abuse in the event of an overdose, rather than an efficacious benefit toward social anxiety. Unlike Holly, the present invention requires the inclusion of an anticholinergic agent, and does not require or envision an antidiarrheal agent. Furthermore, Holly is not directed toward PA or PD as therapeutic indications.
Chow et al. (U.S. Pat. No. 8,012,503) claim a method for enhancing absorption involving a mathematical calculation to derive a theoretical pH for a single API intended for administration to the oral mucosa. Scopolamine and propranolol are disclosed in a lengthy list of APIs for which a theoretical pH may be derived according to the mathematical calculation of the invention.
Hsiao et al. (U.S. Pat. No. 4,755,386) disclose a buccal-adhesive drug delivery technology. Both propranolol and scopolamine are included in a lengthy list of APIs, which may be included as single agents in the buccally-delivered adhesive composition of the invention.
The present invention is focused primarily on fast-acting, mucosally- and orally-delivered pharmaceutical compositions for p.r.n. (“as needed”) treatment of symptoms of panic and acute anxiety, or in anticipation of the symptoms in patients. The compositions consist essentially of an antiemetic antimuscarinic drug and a beta adrenergic receptor antagonist drug, wherein the antimuscarinic drug may be scopolamine and the beta adrenergic receptor antagonist drug may be atenolol, propranolol, pindolol, nadolol, or nebivolol, among other choices.
The present invention is focused on the augmentation of a beta blocker's effects on the cardiovascular system's symptoms of acute anxiety or panic with an antiemetic antimuscarinic agent's effects on non-cardiovascular symptoms of acute anxiety or panic. The term “anxiety” covers a vast breadth of definitions and symptoms. The present invention addresses all or most of the symptoms of acute anxiety or panic episodes, neither of which is addressed by an “off-label” beta blocker alone or an antiemetic antimuscarinic agent alone. The present invention can achieve desirable pharmacologic effects upon a diverse array of cardiovascular and non-cardiovascular symptoms at appropriate doses of APIs that are antiemetic, non-sedating, fast-acting, and coincidentally without the use of addictive drugs and/or Controlled Substances as APIs. Furthermore, augmentation of a beta blocker (i.e., cardiovascular effects) with an antiemetic agent that only affects the symptoms of nausea, vomiting, and/or motion sickness per se provides anxiolytic superiority over a beta blocker alone or an antiemetic agent alone.
Propranolol is the most thoroughly studied of the beta blockers, and serves as the prototype for this class of drugs. Propranolol (or a pharmaceutically acceptable salt thereof) is a beta adrenergic receptor antagonist to reduce cardiac symptoms (e.g., tachycardia and hypertension) resulting from epinephrine in the circulation. Beta blockers interfere with receptor binding by catecholamines, epinephrine and norepinephrine, of which epinephrine is the principal catecholamine affecting the cardiac symptoms. Propranolol is a lipophilic beta blocker that readily crosses the blood-brain barrier. Therefore, it affects both somatic and CNS target tissues. Propranolol can be absorbed mucosally, as demonstrated by sublingual delivery [13], and its bioavailability is higher when absorbed by this route rather than orally [14, 15]. Also, propranolol has been delivered by rectal administration in mammals [16]. It does not demonstrate chemical dependence or sedation that are common side effects of many psychiatric medications.
Propranolol is prescribed for the treatment of various cardiovascular indications (with U.S. FDA approval), most notably hypertension, arrhythmia, angina, as well as prophylaxis of migraines. However, there is some evidence that it might also have some benefit with regard to a subset of the symptoms of panic and acute anxiety, although this is disputed. The drug's anxiolytic potential was recognized as early as 1966, “Emotions are expressed through the autonomic nervous system, and anxiety states are associated with increased secretion of catecholamines. Propranolol may therefore have a place in the treatment of anxiety, especially when the symptoms are related to the cardiovascular system.” [17] This prescient comment five decades ago was subsequently validated by clinical studies with regard to both aspects: (a) propranolol and other beta blockers have been used off-label in the USA for the prophylaxis of performance anxiety; and (b) the pharmacologic benefits of propranolol and other beta blockers are restricted to the cardiovascular system effects per se. The beneficial anxiolytic effects are limited to blocking the pharmacologic effects of catecholamines upon the cardiovascular system without addressing the psychic (CNS) symptoms or other somatic symptoms of acute anxiety and panic, with the possible exception of tremors.
Daily oral propranolol has been demonstrated in one prophylactic study to suppress panic attacks in subjects diagnosed with panic disorder and agoraphobia [18]. Tyrer and Lader demonstrated some effectiveness of oral propranolol in treating somatic anxiety symptoms, but not psychic (mental) anxiety [19, 20]. Another daily oral prophylactic study compared propranolol to oxprenolol and revealed that both beta blockers reduced symptoms of anxiety at one or two weeks duration [21]. However, propranolol was more effective at reducing palpitations when assessed on day 7 compared to oxprenolol. In another clinical study, daily oral propranolol was not effective at treating panic disorder and agoraphobia with panic attacks [22].
There is some evidence suggesting that propranolol might be beneficial in academic test-taking among normal and anxiety-prone students. Examination performance might be increased by pretreatment with this beta blocker [23, 24].
Propranolol has been further studied in clinical trials designed to provoke anxiety. Using the Trier Social Stress Test (TSST) to provoke anxiety in a clinical setting, the somatic and psychic effects of oral propranolol were tested in healthy adult volunteers [25-28]. Propranolol (40 mg) one hour prior to TSST significantly reduced heart rate, reduced systolic blood pressure, and enhanced cognitive flexibility during stress [26]. In another study, propranolol (80 mg) one hour prior to TSST significantly reduced heart rate and increased salivary cortisol, but did not significantly affect BP or subjective stress [25]. In another TSST study, daily oral propranolol (80 mg) did not affect the salivary cortisol response [27]. In a study with healthy volunteer subjects using carbon dioxide inhalation to provoke panic and anxiety, propranolol significantly decreased heart rate, a somatic symptom, but did not provide psychic anxiolytic benefit [29].
Propranolol has also been investigated in patients suffering from severe posttraumatic stress disorder (PTSD). Two clinical studies of this beta blocker have shown possible benefits in the early-stage interventional prevention and subsequent therapy of PTSD [30, 31]. Subsequent reports have also echoed that propranolol might be effective for this condition [32-34], although other reports dispute this conclusion [35, 36].
When considered in aggregate these clinical studies of propranolol, as a well known prototypical beta blocker, provide convincing evidence that the drug can exert somatic (i.e., peripheral) effects on the cardiovascular system in the context of panic and anxiety. With regard to affecting the psychic (CNS) symptoms, the results have been negative, inconsistent, or inconclusive. That being said, there is some limited evidence that propranolol can exert some psychic (CNS) benefits in clinical stress trials. In a pair of clinical studies, propranolol (a central and peripheral beta-blocker) significantly enhanced problem solving during stress, whereas nadolol (peripheral only beta-blocker) and lorezapam (benzodiazepine) did not [37, 38]. Thus, propranolol enhanced cognitive flexibility (“creativity”) during stress. It remains unclear whether propranolol alone can appreciably reduce psychic stress, thus the “need” to complement it with a dissimilar class of pharmacologic agents (e.g., muscarinic receptor antagonists). Thus, augmentation of a beta blocker's limited scope of effects upon the diversity of symptoms of acute anxiety and panic by another pharmacologic class of agents (i.e., antimuscarinic agents) is an essential aspect of the present invention.
The designs of many, if not all, of these historic clinical studies of propranolol might not mirror the conditions of the intended use of the present invention.
Numerous alternative beta blockers are available in lieu of propranolol, for instance atenolol, nadolol, pindolol, and nebivolol, among other choices. One appealing alternative beta blocker is atenolol that has been used to suppress stage fright in performers when administered orally in advance [39]. Atenolol is a beta-1 selective peripheral-acting agent without CNS effects, which should reduce the risk for asthmatic subjects [40]. Oral atenolol at 50-200 mg doses suppresses heart rate by ˜23-24 beats per minute (bpm) vs. ˜10 bpm on placebo [40]. Also, atenolol has been delivered by a mucosal route in mammals [16]. Plus, it was determined during development that sublingual formulations of the present invention containing atenolol do not have a taste and do not produce mouth paresthesia in humans. The latter two properties are unanticipated advantages over the use of propranolol in sublingual dose forms.
Another alternative beta blocker is nadolol, which is non-selective with a preference for beta-1 receptors, and does not pass through the blood-brain barrier. In a clinical trial with musicians, nadolol reduced pulse rate and improved one aspect of performance related to tremor [41]. A similar result was obtained for nadolol in students' singing performance [42]. In spite of being non-selective, nadolol might ironically benefit asthma patients based upon the appropriate dosage, an anti-intuitive result [43].
Another alternative is pindolol, another non-selective beta blocker, which can enhance the effects of co-administered antidepressants and has some 5-HT antagonist property. Pindolol reduced symptoms of performance anxiety in musicians [44].
Another alternative is nebivolol, a third-generation beta blocker. In view of its high degree of beta-1 selectivity, its reduced effect on the airways makes it appealing for patients with chronic obstructive pulmonary disease (COPD) and asthma [45, 46]. Thus, either nebivolol or atenolol might be preferred over the nonselective beta blockers for patients affected by asthma or COPD [47].
Another alternative is betaxolol. Swartz (U.S. Pat. No. 5,798,393) discloses daily oral betaxalol in the treatment of Generalized Anxiety Disorder, PD, and other anxiety-related conditions, stating that “Betaxalol works in 1 to 3 days . . . ” This anxiolytic benefit is prophylactic, as the effects are observed in days, rather than in minutes or hours.
In addition to the already known beta blockers, one can envision a medicinal chemistry approach to develop a structure-activity relationship (SAR) series of cardio-selective compounds (analogs or derivatives) related to beta blockers and/or their active metabolites in vivo, which could be beneficial APIs for compositions of the present invention.
Although the FDA-approved beta blockers are synthetic chemicals, a natural product extract of Eucommia bark and leaves has also been shown to have beta adrenergic receptor antagonist properties [48]. The active ingredients of this Asian herbal extract have not been characterized. This material provides another distinct advantage to the present invention; an over-the-counter (OTC) anxiolytic pharmaceutical composition for acute anxiety or panic could be produced that contains the natural product extract of Eucommia in combination with an OTC antiemetic muscarinic receptor antagonist. Depending on the choice of country, suitable and available OTC antiemetic antimuscarinic agents include diphenhydramine, orphenadrine, doxylamine, meclizine, buclizine, cyclizine, and scopolamine. Thus, dual drug combinations could be used as OTC drug products in certain international markets.
In view of the clinical studies and off-label use of beta blockers, most, if not all psychiatrists are aware that beta blockers can provide some symptomatic relief with regard to performance anxiety [49]. However, many psychiatrists are aware that beta blockers alone do not sufficiently address the aggregate symptoms of panic and acute anxiety, and especially the psychic symptoms thereof (e.g., fear, avoidance, and mental anxiety). Thus, there is a need to couple a beta blocker with another type of active ingredient. This is an essential aspect of the present invention.
Scopolamine (or a pharmaceutically acceptable salt thereof) is a plant-derived natural product that is commonly used for the treatment of motion sickness, nausea, and vomiting. The mechanism of action of this antiemetic drug is as an antagonist of muscarinic acetylcholine receptors. It is a nonselective muscarinic receptor inhibitor that can inhibit all five human receptor subtypes with ˜0.34-5.3 nM Ki values [50]. It is lipophilic and crosses the blood-brain barrier to exert psychic (CNS) pharmacologic effects. Scopolamine (or salt derivatives) is sold by prescription in the USA as a transdermal patch (TRANSDERM SCOP®)) [51]. However, scopolamine is available without a prescription in many foreign markets, where it can be purchased over-the-counter (OTC) or “behind-the-counter” with pharmacist's assistance. For instance, in Australia it is an oral OTC product with a recommended adult dose of 0.3 or 0.6 mg, and a maximum daily dose of 1.2 mg [52]. Scopolamine can also be absorbed mucosally, as demonstrated by sublingual delivery [53, 54].
Scopolamine can also exhibit an antidepressant effect when administered intramuscularly [55], intravenously [56-58] (also disclosed in PCT International Publication No. WO 2006/127418), or orally [59]. Thus, scopolamine can affect at least one mood disorder (i.e., depression), which coincidentally is a co-morbid condition in many persons affected by panic disorder. Another muscarinic receptor antagonist, orphenadrine and its major metabolite, tofenacine, have also been reported to exhibit an antidepressant effect [60-62]. Although depression per se is not the intended medical indication of the present invention, selected antimuscarinic agents can display psychic (CNS) pharmacologic effect(s), such as the treatment and/or prophylaxis of depression (e.g., major depressive disorder, MDD).
Although not common knowledge among physicians at present, there is some historic evidence that scopolamine can exert anxiolytic effect(s). Scopolamine was described a century ago to have a “calming effect” (verbatim) when injected hypodermically into patients afflicted by various psychiatric disorders at doses of 0.2-1.0 mg, which are still relevant human doses to this day [63]. This 1906 publication mentioned, “ . . . the calming effect of the medicament . . . . The action of scopolamine shows itself rapid in maniacal excitement and in acute hallucinatory delirium. The patients become calm gradually, and fall asleep if the dose is somewhat larger.”
A genetic study of the human M2 muscarinic receptor gene (CHRM2) has revealed an association between specific genetic polymorphisms and the risk of depression in major depressive syndrome [64]. Consistent with these pharmacologic and genetic findings in humans, laboratory studies with rodent models for antidepressant activity using both pharmacologic and gene knock-out approaches revealed that the antidepressant-like effects of scopolamine are mediated via the M1 and/or M2 receptors, but not the M3, M4, and M5 receptors [50]. Thus, the human M2 (and/or M1) receptor-linked second messenger signaling pathways in the CNS are likely to affect mood and mood disorders (e.g., depression).
Of relevance to our dual drug approach for acute anxiety and panic, a report disclosed the cardiovascular effects of oral atenolol (50 mg), oral scopolamine HBr (0.3 mg), coincident administration of both drugs, and no treatment in healthy volunteers when exposed to heat within a sauna [12]. Coincident administration of the two oral drugs revealed essentially the same cardiovascular effects as the beta blocker atenolol alone (i.e., reduced heart rate and blood pressure), and either at baseline prior to heat exposure or during it. A relevant antiemetic oral dose of scopolamine alone or as an adjunct to atenolol displayed essentially no effect with regard to the cardiovascular symptoms. Thus, the cardiovascular effects were due to atenolol. The potential for any psychiatric and/or psychic (CNS) effects of scopolamine were not envisioned or addressed by this study.
In view of these results [12] and given that acute anxiety and panic are driven physiologically in part by increased epinephrine's effects on the cardiovascular system, it is appropriate to include a beta blocker (e.g., atenolol) to address the cardiovascular symptoms per se. Scopolamine alone would not be anticipated to be of benefit for the cardiovascular symptoms of these psychiatric conditions. Palpitations resulting from elevated heart rate and/or blood pressure are considered the predominant symptom that patients are aware of during panic attacks and acute anxiety episodes. The beta blocker within the combinations of the present invention can address this primary (major) symptom.
The combination therapies of the present invention may also be of use in other psychiatric disorders, such as alcohol addiction and/or withdrawal, drug addiction and/or withdrawal, migraine, headache, and aggression.
The abuse of alcohol, prescription drugs, and illegal drugs (e.g., opioids/opiates and cocaine) are major mental health care concerns. The repetitive abuse of these chemicals can produce physiologic dependence, tolerance, and addiction. The symptoms of sudden withdrawal depend upon the abused substance, the impairment of neurological and neuroendocrine pathways, as well as visceral and peripheral somatic organ impairment. The withdrawal from addictive substances produces an array of acute symptoms, many of which overlap with the symptoms of panic and acute anxiety. Delirium tremens (DTs) occurs in some alcoholics upon abrupt cessation of drinking. The symptoms of alcohol-related DTs are very similar to those of panic attacks, and are in part related to beta adrenergic effects. The DTs can have serious and even life-threatening consequences. The standards-of-care for DTs are oral benzodiazepines. Withdrawal from opioid and/or opiate addiction is physiologically distinct from alcohol withdrawal.
With regard to beta blockers in substance abuse, atenolol has been shown in placebo-controlled trials to be beneficial in alcohol withdrawal [65-67]. Pindolol has been used to treat alcohol withdrawal [68]. Timolol had a minimal effect on a subset of symptoms of patients experiencing alcohol withdrawal [69]. With regard to beta blockers in cocaine abuse, propranolol has been used to treat withdrawal and overdoses [70, 71]. Note that propranolol has also been shown to suppress tremors [72], consistent with one of the perceived benefits of beta blockers in performance anxiety in musicians (above).
Alcohol dependence has been genetically linked to the human CHRM2 gene encoding the M2 muscarinic receptor (as also demonstrated for depression). Scopolamine has an M1 receptor preference over M2, but it can also bind the M2 receptor [50, 64]. Thus, there is a convergence between the genetic linkage and the pharmacologic studies, thereby providing a rationale for the use of scopolamine (or other muscarinic receptor antagonists) in treating alcohol addiction and/or withdrawal.
The prevalence of migraine in the USA according to the American Migraine Prevalence and Prevention (AMPP) study is 11.7% and probable migraine is 4.5%, for a combined total of 16.2% [73]. The rate is higher in females than in males. The dual drug approach of the present invention may be appropriate for the treatment of migraine and severe headache indications. Migraine is a co-morbid condition in approximately two-thirds of patients suffering from panic disorder [6, 74]. According to Smitherman and coworkers, “The first-line migraine prophylactics are not indicated for PD, and the selective serotonin re-uptake inhibitors used to treat PD are not efficacious for migraine; thus, separate agents are often required to address each condition.”[6] Consistent with that comment, according to Marazziti and coworkers, “ . . . the comorbidity of headache with panic disorder renders this condition more severe and possibly responsive to different treatments compared to panic disorder alone.”[75] These two groups of authors are unaware of a single therapy that affects both migraine and PD. But, it is feasible that a combination of a beta blocker plus a muscarinic receptor antagonist may provide therapeutic benefit for both conditions—panic and migraine.
Beta-adrenergic receptor antagonists (e.g., atenolol, propranolol, metoprolol, nebivolol, nadolol) are considered to be effective prophylactics for chronic or episodic migraine [76-81]. Although one study reported no benefit from propranolol for treatment of acute symptoms [82], there is some, albeit limited, evidence that beta adrenergic receptor antagonists, especially when delivered mucosally, can also have benefit in the therapy of acute migraine [83, 84].
A patent by Innes (U.S. Pat. No. 4,532,244) suggests that transdermally-delivered scopolamine in a patch might be a prophylactic for migraine. However, the unconvincing evidence provided therein was based upon a single patient who used a scopolamine patch for 30 days. However, the biomedical literature is silent regarding whether scopolamine might be of benefit in preventing or treating migraine. Another muscarinic receptor antagonist, buclizine, is an API in an OTC combination drug (MIGRALEVE®) sold in the United Kingdom for the treatment of migraine.
The dual drug combination of the present invention may be therapeutic for migraine or headache, and especially so when delivered rapidly, for instance mucosally (e.g., sublingually).
In an embodiment, the dual drug approach of the present invention may be effective as a treatment for aggression. Systemic adrenaline can produce excited, anxious, and aggressive behavior in some individuals. Propranolol has been shown to have a therapeutic effect with regard to aggressive behavior [85, 86]. Augmentation of a beta blocker with the “calming effect” of scopolamine or another antimuscarinic agent may provide an effective medication for reducing aggression. For instance, scopolamine has been shown to reduce aggressive behavior in nonhuman primates under certain environmental circumstances [87].
The pharmaceutical standard-of-care for PA, PD, anxiety, and anxiety-related disorders by psychiatrists (and some other physicians) involves oral daily maintenance medication, whereas the present invention involves administration “as needed” (p.r.n.), and preferably on an occasional basis.
The pharmaceutical standard-of-care for PA, PD, anxiety, and anxiety-related disorders by psychiatrists (and some other physicians) is intended essentially for the long-term prophylaxis of episodes, whereas the present invention is intended for the short-term treatment of symptoms of episodes as they occur or immediately prior to an anticipated episode.
The pharmaceutical standard-of-care for PA, PD, anxiety, and anxiety-related disorders by psychiatrists (and some other physicians) includes SSRIs and/or benzodiazepines, none of which is the focus of the present invention. The common SSRIs and/or benzodiazepines can exhibit unwanted side effects, not anticipated by the dual drug combinations of the present invention.
Although many psychiatrists (and some other physicians) are aware of off-label (i.e., not FDA-approved) use of beta blockers as prophylactics for performance anxiety (e.g., stage fright during musical performances), the pharmaceutical standard-of-care for PA, PD, anxiety, and anxiety-related disorders by these physicians does not routinely include the use of beta blockers. Beta adrenergic receptor antagonists can provide limited benefit, such as the suppression of tachycardia, palpitations, and increased blood pressure, which are symptoms of panic and acute anxiety. These beta adrenergic receptor antagonist medications are typically administered for the treatment of hypertension. Thus, even though many psychiatrists are familiar with the off-label use of beta blockers for performance anxiety, as stated by Zamorski and Albucher, “Beta blockers, once widely touted as effective antipanic medications, have proven disappointing as monotherapy in subsequent placebo-controlled trials.” [9]
There is a need to augment the limited benefits of a beta blocker (i.e., cardiovascular properties) with another type of active ingredient to produce a superior anti-panic or anti-anxiety therapy for use p.r.n. Furthermore, it would be advantageous for the other agent (i.e., non-beta blocker) to exert some psychic (CNS) pharmacologic benefit(s).
The pharmaceutical standard-of-care for PA, PD, anxiety, and anxiety-related disorders by psychiatrists (and some other physicians) does not include scopolamine. Prescription or over-the-counter (OTC) antiemetic medications acting as muscarinic receptor antagonists can suppress nausea, vomiting, sweating, motion sickness, sea sickness, morning sickness in pregnancy, some of which are symptoms of panic or acute anxiety. However, the transdermal patch of scopolamine does not provide suitable pharmacokinetics for rapid therapy of psychic or somatic symptoms that are the focus of the present invention[51]. Furthermore, some of the antiemetic APIs exhibit coincident antihistamine properties. Examples of the latter are diphenhydramine and meclizine.
Thus, in view of the foregoing, it follows that a pharmaceutical composition consisting essentially of a beta adrenergic receptor antagonist and a muscarinic receptor antagonist are not in use by psychiatrists, other physicians, or other prescribers (e.g., veterinarians or dentists) for treating PA, PD, anxiety, and anxiety-related disorders in particular, or any psychiatric condition for that matter in general. Outside of the present invention, we have found no evidence in the prior art of this particular type of dual drug combination therapy in use at present by psychiatrists, other physicians, or other prescribers for any therapeutic or prophylactic psychiatric indication(s) in humans or other mammals. Also, outside of the present invention, we have found no evidence in the prior art of a psychiatric therapy consisting essentially of a beta blocker and a muscarinic receptor antagonist agent together within a single pharmaceutical composition, or alternatively of coincident simultaneous administration of a pair of compositions, wherein one composition contains the beta blocker and the other contains the muscarinic receptor antagonist agent. Furthermore, these conclusions occur even though both classes of APIs (beta blockers and antimuscarinics) have been in commercial use for over five decades.
Furthermore, the pharmaceutical standard-of-care for PA, PD, anxiety, or anxiety-related disorders by psychiatrists and other physicians does not typically involve administration via a mucosal route, whereas the pharmaceutical compositions of the present invention may be delivered by this route, in addition to the oral route. The mucosal routes are especially useful and may be preferred in cases when “time is of the essence” in producing a pharmacologic effect and/or when the patient is unwilling or unable to swallow an oral solid or liquid dose form, or to be injected a parenteral dose form. Thus, mucosal delivery is an additional distinct benefit to the dual drug compositions of the present invention.
A dual drug combination is a well-known regulatory paradigm in the USA. There are ample predicate FDA-approved prescription drugs that contain two or more APIs. A common example is PERCOCET®, a combination of oxycodone and acetaminophen. Two additional recently-approved examples are NUDEXTA®, a combination of dextromethorphan and guinidine, and HARVONI®, a combination of ledipasvir and sofosbuvir. In addition, FDA-approved OTC drugs frequently contain more than one API.
Prior to the present invention there was a need for fast-acting (e.g., mucosally-delivered) pharmaceutical compositions for immediate p.r.n. treatment of acute symptoms of panic and acute anxiety. The present invention provides suitable solutions for this previously unmet medical need, and with the additional benefits of the APIs not being addictive and/or Controlled Substances.